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Synthetic Pathways to NHC Precursors in Organometallic Chemistry

Explore various synthetic pathways to N-heterocyclic carbene (NHC) precursors for organometallic chemistry, including cyclization methods and applications as ligands.

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Synthetic Pathways to NHC Precursors in Organometallic Chemistry

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  1. Reporter: Zhang Lei Supervisor: Prof. Mo Date: 2016-11-11

  2. Outline 1. Introduction 2. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom 2.2 Ring Closing by the Final Introduction of the Backbone 2.3 Final Introduction of the Amino Moiety 3. Conclusion

  3. Outline 1. Introduction 2. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom 2.2 Ring Closing by the Final Introduction of the Backbone 2.3 Final Introduction of the Amino Moiety 3. Conclusion

  4. Introduction Vincent César Born in 1977 in Nancy, France. Now，CNRS researcher at the “Laboratoire de Chimie de Coordination du CNRS” in Toulouse. His research is mainly focused on the design and development of new N-heterocyclic carbenes for organometallic chemistry and homogeneous catalysis.

  5. Introduction • Definition • History 1962 Finding Wanzlick [1] 1970s and 1980s Extensive work Lappert [4] 1991 Isolation and full characterization Arduengo [6] 1968 Using as ligands Wanzlick [2] and Öfele [3] 1988 First stable NHC carbine Bertrand [5] [1]Wanzlick, H.-W. Angew. Chem., Int. Ed. Engl. 1962, 1, 75. [2] Wanzlick, H.-W.; Schönherr, H. J. Angew. Chem., Int. Ed. Engl. 1968, 7, 141. [3] Öfele, K. J. Organomet. Chem. 1968, 12, 42. [4] For reviews, see: (a) Cardin, D. J.; Cetinkaya, B.; Lappert, M. F.Chem.Rev. 1972,72, 545.(b) Lappert, M. F. J. Organomet. Chem. 1988, 358, 185. [5] Igau, A.; Grützmacher, H.; Baceiredo, A.; Bertrand, G. J. Am. Chem. Soc. 1988, 110, 6463. [6] Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361.

  6. Introduction • Electronic character nitrogen centers σ-electron-withdrawing and π-electron-donating character electron-rich nucleophilic species form stronger bonds with metal centers • Structure character better steric protection

  7. Introduction • Applications as ubiquitous ligands in organometallic chemistry as excellent nucleophilic organocatalysts • Methods of synthesis

  8. Introduction • Other methods • Reduction of thiourea with molten potassium in boiling THF [1] • Vacuum pyrolysis of an NHC-volatile compound adduct (like MeOH, • CHCl3, CHF3, C6F5H) [2] [1] Denk, M. K.; Hezarkhani, A.; Zheng, F. L. Eur. J. Inorg. Chem. 2007, 3527. [2] Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. Chem.;Eur. J. 2004, 10, 4073.

  9. Introduction • Other methods (iii) In situ release of NHC from NHC-CO2 or NHC-metal (SnII, MgII, ZnII) adducts [1] (iv) Reduction of a chloroformamidinium salt with Hg(TMS)2 or with Pd(0) and Ni(0) complexes [2] [1] Voutchkova, A. M.; Appelhans, L. N.; Chianese, A. R.; Crabtree, R. H. J. Am. Chem. Soc. 2005, 127, 17624. [2] Otto, M.; Conejero, S.; Canac, Y.; Romanenko, V. D.; Rudzevitch, V.; Bertrand, G. J. Am. Chem. Soc. 2004, 126, 1016.

  10. Introduction • General synthetic pathways to NHC precursors • Ring closure by introduction of the precarbenic unit • Ring closure by linkage of the backbone to the preassembled precarbenic and amino units • Ring closure by introduction of the amino moiety

  11. Outline 1. Introduction 2. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom 2.2 Ring Closing by the Final Introduction of the Backbone 2.3 Final Introduction of the Amino Moiety 3. Conclusion

  12. Outline 1. Introduction 2. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom 2.2 Ring Closing by the Final Introduction of the Backbone 2.3 Final Introduction of the Amino Moiety 3. Conclusion

  13. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • 1,1-Bis(electrophile) Compounds as C1 Providers • Using Paraformaldehyde as the Precarbenic Unit • Cyclization via a Preinstalled Formamide

  14. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • 1,1-Bis(electrophile) Compounds as C1 Providers • Using Paraformaldehyde as the Precarbenic Unit • Cyclization via a Preinstalled Formamide

  15. Synthetic Pathways to NHC Precursors • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit The first report Saba, S.; Brescia, A.-M.; Kaloustian, M. K. Tetrahedron Lett. 1991, 32, 5031.

  16. Synthetic Pathways to NHC Precursors • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • Condensation-Reduction Route • Bisacylation/Reduction Route • Acylation-Alkylation/Reduction Route • Starting from a Preformed Diamine Core • Reaction on a Bis-electrophilic Core • R-Amino Acids as Building Blocks • Triazolium Salts and Benzoxazolium

  17. Synthetic Pathways to NHC Precursors • Condensation-Reduction Route Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55, 14523.

  18. Synthetic Pathways to NHC Precursors • Condensation-Reduction Route

  19. Synthetic Pathways to NHC Precursors • Condensation-Reduction Route Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954.

  20. Synthetic Pathways to NHC Precursors • Condensation-Reduction Route [1] [3] [2] [1] Alcarazo, M.; Roseblade, S. J.; Alonso, E.; Fernandez, R.; Alvarez, E.; Lahoz, F. J.; Lassaletta, J. M. J. Am. Chem. Soc. 2004, 126, 13242. [2] Enders, D.; Meiers, M. Synthesis 2002, 2542. [3] Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693.

  21. Synthetic Pathways to NHC Precursors • Bisacylation/Reduction Route [1] [2] [1] Dinger, M. B.; Nieczypor, P.; Mol, J. C. Organometallics 2003, 22, 5291. [2] Yun, J.; Marinez, E. R.; Grubbs, R. H. Organometallics 2004, 23, 4172.

  22. Synthetic Pathways to NHC Precursors • Bisacylation/Reduction Route

  23. Synthetic Pathways to NHC Precursors • Acylation-Alkylation/Reduction Route [1] [2] [1] Paczal, A.; Bényei, A. C.; Kotschy, A. J. Org. Chem. 2006, 71, 5969. [2] Chung, C. K.; Grubbs, R. H. Org. Lett. 2008, 10, 2693.

  24. Synthetic Pathways to NHC Precursors • Starting from a Preformed Diamine Core [1] [2] [1] Huynh, H. V.; Han, Y.; Jothibasu, R.; Yang, J. A. Organometallics 2009, 28, 5395. [2] Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225.

  25. Synthetic Pathways to NHC Precursors • Starting from a Preformed Diamine Core [2] [1] [1] Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877. [2] Min, K. S.; Weyermuller, T.; Bothe, E.; Wieghardt, K. Inorg. Chem. 2004, 43, 2922.

  26. Synthetic Pathways to NHC Precursors • Starting from a Preformed Diamine Core

  27. Synthetic Pathways to NHC Precursors • Reaction on a Bis-electrophilic Core [1] [3] [2] [1] Jurcík, V.; Gilani, M.; Wilhelm, R. Eur. J. Org. Chem. 2006, 5103. [2] Steinke, T.; Shaw, B. K.; Jong, H.; Patrick, B. O.; Fryzuk, M. D. Organometallics 2009, 28, 2830. [3] Leuthäusser, S.; Schmidts, V.; Thiele, C. M.; Plenio, H. Chem.;Eur. J. 2008, 14, 5465.

  28. Synthetic Pathways to NHC Precursors • Reaction on a Bis-electrophilic Core [1] [3] [2] Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673.

  29. Synthetic Pathways to NHC Precursors • Reaction on a Bis-electrophilic Core [2] [1] [1] Tennyson, A. G.; Rosen, E. L.; Collins, M. S.; Lynch, V. M.; Bielawski, C. W. Inorg. Chem. 2009, 48, 6924. [2] Saravanakumar, S.; Kindermann, M. K.; Heinicke, J.; Köckerling, M. Chem. Commun. 2006, 640.

  30. Synthetic Pathways to NHC Precursors • R-Amino Acids as Building Blocks Tiede, S.; Berger, A.; Schlesiger, D.; Rost, D.; Lühl, A.; Blechert, S. Angew. Chem., Int. Ed. 2010, 49, 3972.

  31. Synthetic Pathways to NHC Precursors • Triazolium Salts and Benzoxazolium [1] [2] [1] Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891. [2] Ma, Y.; Wei, S.; Lan, J.; Wang, J.; Xie, R.; You, J. J. Org. Chem. 2008, 73, 8256.

  32. Synthetic Pathways to NHC Precursors • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • Using trialkyl orthoformate • Acidic conditions • A well-developed procedure • Applicable to imidazolinium, benzimidazolium, tetrahydropyrimidinium • Each methods having its own advantages and limitations

  33. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • 1,1-Bis(electrophile) Compounds as C1 Providers • Using Paraformaldehyde as the Precarbenic Unit • Cyclization via a Preinstalled Formamide

  34. Synthetic Pathways to NHC Precursors • 1,1-Bis(electrophile) Compounds as C1 Providers

  35. Synthetic Pathways to NHC Precursors • gem-Dihalides as C1 Building Blocks [1] [2] [1] Calder, I. C.; Spotswood, T. M.; Sasse, W. H. F. Tetrahedron Lett. 1963, 2, 95. [2] Nonnenmacher, M.; Kunz, D.; Rominger, F.; Oeser, T. Chem. Commun. 2006, 1378.

  36. Synthetic Pathways to NHC Precursors • Using Weiss' Reagent Weiss, R.; Reichel, S.; Handke, M.; Hampel, F. Angew. Chem., Int. Ed. 1998, 37, 344.

  37. Synthetic Pathways to NHC Precursors • Using Chloromethyl Ethers Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55, 14523.

  38. Synthetic Pathways to NHC Precursors • Using Chloromethyl Pivalate Würtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523.

  39. Synthetic Pathways to NHC Precursors • Using Chloromethyl Pivalate

  40. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • 1,1-Bis(electrophile) Compounds as C1 Providers • Using Paraformaldehyde as the Precarbenic Unit • Cyclization via a Preinstalled Formamide

  41. Synthetic Pathways to NHC Precursors • Using Paraformaldehyde as the Precarbenic Unit

  42. Synthetic Pathways to NHC Precursors • Imidazolium Salts [1]Bildstein, B.; Malaun, M.; Kopacka, H.; Wurst, K.; Mitterbück, M.; Ongania, K.-H.; Opromolla, G.; Zanello, P. Organometallics 1999, 18, 4325. [2] Nolan, S. P. U. S. Patent 7,109,348, 2006; (b) Jafarpour, L.; Stevens, E. D.; Nolan, S. P. J. Organomet. Chem. 2000, 606, 49.

  43. Synthetic Pathways to NHC Precursors • Imidazolium Salts [1] Hintermann, L. Beilstein J. Org. Chem. 2007, 3, 22. [2] Ogle, J. W.; Zhang, J.; Reibenspies, J. H.; Abboud, K.; Miller, S. A. Org. Lett. 2008, 10, 3677.

  44. Synthetic Pathways to NHC Precursors • Via Oxidation of a Cyclic Aminal [1] Mayr, M.; Wurst, K.; Ongania, K.-H.; Buchmeiser, M. R. Chem.; Eur. J. 2004, 10, 1256. [2] Mayr, M.; Buchmeiser, M. R. Macromol. Rapid Commun. 2004, 25, 231.

  45. Synthetic Pathways to NHC Precursors • Via Oxidation of a Cyclic Aminal [1] Bildstein, B.; Malaun, M.; Kopacka, H.; Ongania, K.-H.; Wurst, K. J. Organomet. Chem. 1999, 572, 177. [2] Schwarz, D. E.; Cameron, T. M.; Hay, P. J.; Scott, B. L.; Tumas, W.; Thorn, D. L. Chem. Commun. 2005, 5919.

  46. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom • Trialkyl Orthoformate (HC(OR)3) as the Precarbenic Unit • 1,1-Bis(electrophile) Compounds as C1 Providers • Using Paraformaldehyde as the Precarbenic Unit • Cyclization via a Preinstalled Formamide

  47. Synthetic Pathways to NHC Precursors • Cyclization via a Preinstalled Formamide [1]Alcarazo, M.; Roseblade, S. J.; Cowley, A. R.; Fernandez, R.; Brown, J. M.; Lassaletta, J. M. J. Am. Chem. Soc. 2005, 127, 3290. [2] Dorn, H.; Zubek, A.; Hilgetag, G. Chem. Ber. 1965, 98, 3377.

  48. Outline 1. Introduction 2. Synthetic Pathways to NHC Precursors 2.1 Cyclization by Introduction of the Precarbenic Atom 2.2 Ring Closing by the Final Introduction of the Backbone 2.3 Final Introduction of the Amino Moiety 3. Conclusion

  49. Synthetic Pathways to NHC Precursors 2.2 Ring Closing by the Final Introduction of the Backbone • Condensation onto an Aminal Moiety • Cyclization Starting from a N,N’ -Disubstituted Formamidine • Cyclization by Quaternization of an Imine • Cyclization Starting from a N,P-Disubstituted Phosphaformamidinate • Cyclization Starting from a Thioformamide

  50. Synthetic Pathways to NHC Precursors • Condensation onto an Aminal Moiety Arduengo, A. J., III U.S. Patent 5,077,414, 1991.

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